US8267982B2 - Photodynamic cellular and acellular organism eradication utilizing a photosensitive material and surfactant - Google Patents

Photodynamic cellular and acellular organism eradication utilizing a photosensitive material and surfactant Download PDF

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US8267982B2
US8267982B2 US09/792,578 US79257801A US8267982B2 US 8267982 B2 US8267982 B2 US 8267982B2 US 79257801 A US79257801 A US 79257801A US 8267982 B2 US8267982 B2 US 8267982B2
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photosensitive material
light
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Merrill A. Biel
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Advanced Photodynamic Technologies Inc
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Advanced Photodynamic Technologies Inc
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Priority to US09/139,866 priority Critical patent/US6251127B1/en
Priority to US09/514,070 priority patent/US7229447B1/en
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Assigned to ADVANCED PHOTODYNAMIC TECHNOLOGIES, INC. reassignment ADVANCED PHOTODYNAMIC TECHNOLOGIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIEL, MERRILL A.
Priority claimed from US10/026,198 external-priority patent/US8187278B2/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0057Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0076PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/54Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0009Inactivation or decontamination of a medicinal preparation prior to administration to the animal or human, e.g. : inactivation of viruses or bacteria for vaccines, sterilisation by electromagnetic radiation
    • A61K41/0019Inactivation or decontamination of a medicinal preparation prior to administration to the animal or human, e.g. : inactivation of viruses or bacteria for vaccines, sterilisation by electromagnetic radiation by UV, IR, Rx or gamma rays
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0057Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0057Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines

Abstract

The invention relates to a method of photoeradication of cellular and acellular organisms including the steps of providing a surface acting agent in association with a cellular or acellular organism, the surface acting agent disorienting a membrane structure so that said membrane no longer functions as an effective osmotic barrier; providing a photosensitive material in association with the cellular or acellular organism; and applying light in association with the cellular or acellular organism to cause a disruption of the organism. The method according to the present invention may be utilized in invitro and invivo treatment protocols for infections, sterilization procedures, cancer cell eradication, virus and fungus eradication, spore eradication, and biofilm organism eradication. Additional aspects of the invention include particular combinations of photosensitive materials and surfactants for use in photodynamic therapies.

Description

RELATED APPLICATIONS

This application claims the benefit of priority, pursuant to 35 U.S.C. §119-120, from copending application Ser. Nos. 09/139,866 filed Aug. 25, 1998, and 09/514,070 filed Feb. 26, 2000.

FIELD OF THE INVENTION

The invention relates to a photodynamic therapy (PDT) or process, and more particularly to a photodynamic therapy or process utilizing a photosensitive material and a chemical agent, such as a surfactant material, for in vitro and in vivo cellular and acellular organism eradication. The invention also relates to photodynamic eradication of bacteria, fungal, and viral wound infections and sterilization of tissue using a photosensitive material, such as methylene blue or toluidene blue, and a surfactant material, such as polymyxin B, SDS, or cetrimide. Additionally, the invention relates to photodynamic eradication of cancer cells, such as present within a tumor, by PDT in conjunction with a photosensitive material and a surfactant. The present invention advantageously uses light energy in combination with a photosensitive material and a surfactant material to treat both in vitro and in vivo pathogens, including cancer cells and microbiological pathogens. The invention also relates to the eradication or destruction of biofilms via a photodynamic mechanism. The invention further relates to the eradication of spores in both in vivo and in vitro applications.

BACKGROUND OF THE INVENTION

Abnormal cells and acellular organisms are known to selectively absorb certain dyes (photosensitive materials) delivered to a treatment site to a more pronounced extent than surrounding tissue. Once presensitized, abnormal cells or acellular organisms can be destroyed by irradiation with light of an appropriate wavelength corresponding to an absorbing wavelength of the photosensitive material, with minimal damage to surrounding normal tissue. This procedure, which is known as photodynamic therapy (PDT), has been clinically used to treat metastatic breast cancer, bladder cancer, head and neck cancers, and other types of malignant tumors.

U.S. Pat. No. 5,676,959 to Heitz et al., purportedly discloses an ingestible phototoxic insecticidal composition including a photoactive dye, an attractant compound and/or feeding stimulant, and an adjuvant, whereby the adjuvant interacts with the photoactive dye and insect gastrointestinal (GI) tract to facilitate transport of the phototoxic insecticide across the GI tract. The use of an adjuvant to facilitate pharmaceutical uptake via GI tract absorption is known in the art. Unlike the surface acting agents of the Applicant's present invention, these adjuvants do not produce a disorientation of a cell membrane so that the cell membrane no longer functions as an effective osmotic barrier.

The article “Inactivation of Gram-Negative Bacteria by Photosensitized Porphyrins” by Nitzan, et al., published in Photochemistry and Photobiology, Vol. 55, No. 1, pp. 89-96, 1992, purportedly discloses the use of polycationic agent polymyxin nonapeptide (PMNP) in association with a photoactive agent, deuteroporphyin (DP). PMNP is disclosed to disturb the outer membrane of a gram-negative bacteria so as to permit access of the DP to bind to the internal lipoprotein osmotic membrane of the bacterial cell. PMNP is disclosed to only disturb the outer membrane structure and not its function, and not cause metabolic leakage from the cells (or osmotic changes in the cell). Unlike the surface acting agent of the Applicant's present invention, PNMP does not produce a disorientation of a cell membrane so that the cell membrane no longer functions as an effective osmotic barrier. In the Applicant's present invention, the surface acting agent causes a disorientation of the cell membrane thereby compromising the effective osmotic membrane barrier and thus allowing the photosensitizer to diffuse through the compromised cell membrane into the cell.

U.S. Pat. No. 5,616,342, to Lyons, purportedly discloses an emulsion comprising a lipid, a poorly water-soluble photosensitizing compound, a surfactant, and a cosurfactant. Poorly water-soluble photosensitizers are disclosed to pose serious challenges to achieving suitable formulation for administration to the body. Lyons '342 discloses that surfactants facilitate the preparation of the emulsion by stabilizing the dispersed droplets of an oil-in-water emulsion, and that the use of surfactants in combination with poorly water-soluble pharmacologic compounds is known in the art. Unlike the surface acting agents of the Applicant's present invention, the surfactant in Lyons does not produce a disorientation of a cell membrane so that the cell membrane no longer functions as an effective osmotic barrier.

SUMMARY OF THE INVENTION

The present invention provides a method of photoeradication of cells and acellular organisms, such as during an in vitro or in vivo disinfection or sterilization procedure, or for cancer cell or acellular organism eradication. In one embodiment, the method utilizes a combination of a photosensitive material and a chemical agent, such as a surfactant material, in a solution. The invention additionally provides a method of dispensing a combined solution at or near the tissue site and subsequently irradiating the tissue site with light at a wavelength absorbed by the photosensitive material. The invention also relates to an apparatus or kit assembly including a surfactant material and a photosensitive material. Yet another aspect of the present invention is the eradication or destruction of biofilms via a photodynamic mechanism.

The invention also relates to a use of a photosensitizing material, such as methylene blue or toluidene blue, in combination with a surfactant compound, such as polymyxin B, SDS or cetrimide, in a PDT treatment protocol against bacterial, fungal, acellular organism infections, and/or for cancer cell photoeradication. A treatment device is configured to deliver light energy to the area of infection or cancer cell activity at wavelengths ranging from about 450 nm to about 850 nm; provide a dosage rate ranging from about 0 to about 150 mw/cm2; and provide a light dose ranging from 0 to about 300 J/cm2.

The use of a photosensitive material, such as methylene blue or toluidene blue, combined with a surfactant material, such as SDS, polymyxin B, or cetrimide, in a photodynamic therapy advantageously acts as a broad spectrum antimicrobial, i.e., antibacterial, antiviral, sporicidal, and/or antifungal agent. The photosensitizer/surfactant combination and PDT may be used, for example, before a surgical operation. The present invention advantageously results in the destruction of gram positive and gram negative bacteria and fungus. Importantly, the present invention acts to destroy antibiotic resistant bacteria as it utilizes a different destruction mechanism than antibiotics.

The invention also relates to a method of treating an infection including identifying an in vivo area of infection; applying or dispensing a concentration including a photosensitive material, such as methylene blue or toluidene blue, and a surfactant, such as polymyxin B, SDS, or cetrimide, to the area of infection; and exposing the area of infection with a light having a light wavelength, light dosage and a light dosage rate. For toluidene blue, the light wavelength may range from about 610 nm to about 680 nm. For methylene blue, the wavelength may range from about 630 nm to about 664 nm. The light dosage may range from about 10 J/cm2 to about 60 J/cm2. The light dosage rate may range from about 50 mw/cm2 to about 150 mw/cm2. The concentration for methylene blue and toluidene blue may range from about 10 μg/ml to about 500 μg/ml. For other photosensitive materials, the preferred wavelength or range may be known or available. The area of infection may include gram positive and gram negative bacteria, fungus, spores, or viruses including, but not limited to, at least one of Staphylococcus sp., Candida albicans, Escherichia coli, Enterococcus sp., Streptococcus sp., Pseudomonus aeruginosa, Hemophilus influenzae, Clostridia sp., Herpes strains, or human immunodeficiency virus (HIV).

The invention also relates to a treatment kit having a solution including at least a combination of a photosensitizing material, such as methylene blue or toluidene blue, and a surfactant material, such as polymyxin B, SDS, or cetrimide. For polymixin B, the concentration ranges may be from about 3 μg/ml to about 500 μg/ml. For SDS and cetrimide, the concentration range may be from 0.005% to 1%. A laser light emitting treatment device may be utilized to effect the photodynamic process, including but not limited to a light source which emits at wavelengths ranging from about 450 nm to about 850 nm; providing a dosage rate ranging from about 0 to about 150 mw/cm2; and providing a light dose ranging from 0 to about 300 J/cm2. Alternative light sources would also be practicable as appreciated by one skilled in the relevant arts.

The invention also relates to a method of treating an infection, an in vitro or in vivo sterilization procedure, or photoeradication of cancer cells, including the steps of providing one or more cells; providing a concentration of combined photosensitive material/surfactant on or near the one or more cells; and applying a light having a wavelength ranging from about 450 nm to about 850 nm; a dosage rate ranging from about 0 to about 150 mw/cm2; and a light dose ranging from 0 to about 300 J/cm2 to the one or more cells wherein the combination of light and photosensitive material is adapted to cause photodestruction of the one or more cells. The one or more cells may be an infection caused by or associated with a bacteria, virus, or fungus. Alternatively, the one or more cells may be cancer cells. Virus infected cells may also be treated in accordance with the present invention. In such instance, a virus within the cell may be specifically eradicated without destruction of the host cell. Obligate intracellular bacterial agents, such as Chlamydia, Rickettsia, and Ehrlichia, may be treated in accordance with the present invention. Other bacteria may also be treated in accordance with the present invention. The one or more cells may be gram positive or gram negative bacteria. The photosensitive material may be methylene blue, toluidene blue, or a combination thereof. The photosensitive material may be monomeric, dimeric, or polymeric.

Another aspect of the present invention is the provision of biofilm reduction and/or eradication. A biofilm is an accumulation of microorganisms including bacteria, fungi and viruses that are embedded in a polysaccharide matrix and adhere to solid biologic and non-biologic surfaces. Biofilms are medically important as they may account for a majority of microbial infections in the body. Biofilms account for many of the infections of the oral cavity, middle ear, indwelling catheters and tracheal and ventilator tubing. The National Institutes of Health estimates that the formation of biofilms on heart valves, hip and other prostheses, catheters, intrauterine devices, airway and water lines and contact lenses has become a $20 billion dollar health problem in the United States. A treatment apparatus and protocol for the reduction and/or eradication of biofilms is another aspect of the present invention.

Biofilms are remarkably resistant to treatment with conventional topical and intravenous antimicrobial agents. The Center for Biofilm Engineering at Montana State University has reported that biofilms may require 100 to 1,000 times the standard concentration of an antibiotic to control a biofilm infection. This is thought to be due to the antibiotic's inability to penetrate the polysaccharide coating of the biofilm. Even more concerning is that biofilms increase the opportunity for gene transfer due to the commingling of microorganisms. Such gene transfer may convert a previous avirulent commensal organism into a highly virulent and possibly antibiotic resistant organism.

Bacteria embedded within biofilms are also resistant to both immunological and non-specific defense mechanisms of the body. Bacterial contact with a solid surface triggers the expression of a panel of bacterial enzymes that cause the formation of polysaccharides that promote colonization and protection of the bacteria. The polysaccharide structure of biofilms is such that immune responses may be directed only at those antigens found on the outer surface of the biofilm and antibodies and other serum or salivary proteins often fail to penetrate into the biofilm. Also, phagocytes may be effectively prevented from engulfing a bacterium growing within a complex polysaccharide matrix attached to a solid surface.

Nosocomial pneumonia is the most prevalent infection in patients who are mechanically ventilated. It is the leading contributor to mortality in patients, accounting for 50% of deaths in patients with hospital acquired infections. The endotracheal tubes (ET) and tracheostomy tubes have long been recognized as a risk factor for nosocomial pneumonia since they bypass host defenses allowing bacteria direct access to the lungs. These tubes are commonly made of polyvinyl chloride, a surface on which local bacteria colonize rapidly to form an adhesive polysaccharide glycocalyx layer. This glycocalyx layer protects bacterial colonies from both natural and pharmacologic antibacterial agents, in effect increasing the virulence of the bacterial species in the intubated host. This phenomenon of biofilm formation has been demonstrated to occur on ET tubes and subsequent dislodgement of biofilm protected bacteria in the lungs by a suction catheter is considered to be a significant factor in the pathogenesis of nosocomial pneumonia. Indeed, in a study of biofilm formation in endotracheal tubes, microbial biofilm was identified by surface electron microscopy in 29 of 30 endotracheal tubes examined. Interestingly, there was no biofilm formation on the outer surface of the ET tube. Biofilm formed exclusively on the luminal surface of all tubes regardless of whether the patients had received broad spectrum antibiotics and was most prevalent around the side hole of the tip region. ET tubes obtained within 24 hours of placement showed large areas of surface activity with adherent bacteria in a diffuse pattern indicating initial colonization of the ET tube. The surface of tubes in place for longer periods had a profuse microbial biofilm. In some instances a large mass of matrix enclosed bacterial cells appeared to project from the confluent accretion on the luminal surface of the ET tube in such a manner that it could be dislodged readily and aspirated into the lower respiratory tract. Pseudomonas species, Staphylococcus aureus, and enteric aerobic bacteria including E. coli, were the most frequently isolated pathogens in the ET tubes in patients that did not receive broad spectrum antibiotics. These also are the pathogenic bacteria most commonly found in nosocomial pneumonia. In patients that received broad spectrum antibiotics yeast species and Streptococcus species were more common.

Evaluations have been made into the relationship of biofilm formation in endotracheal tubes and distant colonization of the pulmonary tree. These evaluations have demonstrated that bacteria from the endotracheal tube biofilm were capable of being cultured from the moisture exchanger and the ventilator tubing up to 45 cm from the tip of the endotracheal tube. Furthermore they demonstrated that contamination of the tracheal tube biofilm with a patient's own gastrointestinal flora provides a mechanism for initial and repeated lung colonization and secondary pneumonia. These life threatening pulmonary infections are perpetuated by microbiological seeding from the tracheostomy and endotracheal tube biofilms and become difficult to treat due to the propensity of the biofilm microorganisms to develop antibiotic resistance.

Methylene blue (MB) based photodynamic therapy has been demonstrated in vitro and in vivo to be effective in the photoeradication of antibiotic resistant gram positive and gram negative bacteria. Methylene blue has a very low tissue toxicity and can be administered to humans orally and intravenously in high doses without any toxic effects. Because of the known low toxicity and its present use and acceptance in medical practice as well as its high photoactive potential this photosensitive material is ideal use in accordance with the present invention for evaluation of its effect on the destruction of bacteria, viruses and fungi. The photoactive dye Methylene blue belongs to the phenothiazine class. Its bactericidal effect is related to its photodynamic properties. This dye is a single pure compound and has a strong absorption at wavelengths longer than 620 nm, where light penetration into tissue is optimal. The absorbance peak of MB is at 664 nm, its optical extinction coefficient is 81600 M−1 cm−1.

The photoactivity of MB results in two types of photooxidations: (i) direct reaction between the photoexcited dye and substrate by hydrogen abstraction or electron transfer creating different active radical products; and (ii) direct reaction between the photoexcited dye in triplet state and molecular oxygen producing singlet oxygen. Both kinds of active generated products are strong oxidizers and they cause cellular damage, membrane lysis, protein inactivation and/or DNA modification.

MB has a high quantum yield of the triplet state formation (˜T=0.52-0.58) and a high yield of the singlet oxygen generation (0.2 at pH 5 and 0.94 at pH 9).

Biofilms are resistant to topical, oral and intravenous antibiotic administration due to the polysaccharide glycocalyx formation that surrounds the bacteria. The polysaccharide coating prevents the antibiotic from penetrating into the biofilms and destroying the bacteria. Methylene blue has the potential ability to destroy biofilms as it selectively binds and penetrates polysaccharides thereby exposing the bacteria in the biofilm to the photodestructive effects of methylene blue. For this reason, methylene blue may be an ideal photosensitizer that may provide a means for the broad spectrum photoeradication of biofilms. The use of a surfactant, such as SDS, can act to both emulsify the biofilm and increase a membrane permeability of an acellular or cellular organism within the biofilm. The combination of a surfactant with a photosensitive material permits the photosensitive material to pass through the biofilm and acellular or cellular organism membrane, and accumulate within the acellular or cellular organism. As a result, a treatment protocol according to the present invention may result in more effective eradication of acellular and cellular organisms within biofilms.

Another object of the present invention is the provision of a treatment protocol utilizing a photosensitive material and surfactant in a pH-selective solution. By adjusting the pH of the solution, an enhanced kill rate of gram-negative or gram-positive bacteria results. The pH of the solution can be determined and adjusted using known processes or agents.

Still other objects and advantages of the present invention and methods of construction of the same will become readily apparent to those skilled in the art from the following detailed description, wherein only the preferred embodiments are shown and described, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments and methods of construction, and its several details are capable of modification in various obvious respects, all without departing from the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a tree structure of organisms.

FIG. 2 is a table of results of photodynamic eradication using a combined solution of methylene blue and the surfactant, SDS.

FIG. 3 is a table of results of photodynamic eradication using methylene blue and SDS in the treatment of oral candidiasis.

FIG. 4A is first page of a table of results of photodynamic eradication of biofilm microorganisms using a photosensitive material and the surfactant.

FIG. 4B is second page of a table of results of photodynamic eradication of biofilm microorganisms using a photosensitive material and the surfactant.

FIG. 5 is a table of results of photodynamic eradication using a pH variable solution of a photosensitive material.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the invention, a photodynamic therapy utilizes a photosensitive material, such as methylene blue or toluidene blue, in combination with a chemical agent, such as surface acting agent or ‘surfactant’, and a light emitting device, such as a light wand, light patch, light pad or shaped light-emitting article such as a mouthpiece to illuminate the site. The photodynamic therapy according to the present invention may be utilized in the eradication of cellular organisms, such as tumor cells, cancer cells, virus-infected cells, bacteria, etc. The photodynamic therapy according to the present invention may also be utilized in the eradication of acellular organisms, defined broadly to include organisms not composed of cells, e.g., bodies of protoplasm made discrete by an enveloping membrane (also referred to a capsule, envelope, or capsid). Examples of acellular organisms include, but are not limited to, viruses, spores, and other virus-like agents such as viroids, plasmids, prions, and virinos, and other infectious particles.

Reference may be made to FIG. 1, wherein component structures of acellular and cellular organisms are presented. Procaryotic cells are cellular organisms, including bacteria. The component structures of procaryotic cells include appendages, cell envelope, and protoplasm. The cell envelope further includes the glycocalyx (capsules, slime layers), cell wall, and cell membrane. All bacteria cells invariably have a cell envelope, glycocalyx, cell membrane, cell pool, ribosomes, and a nucleoid; the majority have a cell wall. Although they are common to many species, flagella, pili, fimbriae, capsules, slime layers, and granules are not universal components of all bacteria. Organisms of the genera Chlamydia, Rickettsia, and Ehrlichea, referred to as obligate intracellular bacteria, are prokaryotes that differ from most other bacteria with respect to their very small size and obligate intracellular parasitism.

Eucaryotic cells are typical of certain microbial groups (fungi, algae, protozoans, and helminth worms) as well as all animal and plant cells. Eucaryotic cells have component structures including appendages, surface structures, cell wall, cytoplasmic membrane, nucleus, cytoplasm, cytoskeleton, and ribosomes. The surface structures may include glycocalyx, capsules, and slimes. Virus particles are not cells and they neither possess procaryotic nor eucaryotic structural qualities. Instead, they are large, complex macromolecules, with parts made up of repeating molecular subunits. Virus particles include component structures of a covering and a central core. The covering includes a capsid and in some viruses, an envelope. All viruses have a protein capsid or shell that surrounds the nucleic acid strand. Members of 12 of the 17 families of animal viruses possess an additional covering external to the capsid called an envelope, which is actually a modified piece of the host's cell membrane. Viruses that lack this envelope are considered naked nucleocapsids. Special virus-like infectious agents include the prion (proteinacious infectious particles) and viroids.

A photosensitive material is defined herein as a material, element, chemical, solution, compound, matter, or substance which is sensitive, reactive, receptive, or responsive to light energy. Photosensitive materials may be pro